The overall goal of this project is directed at gaining a deeper understanding of the basis for the normal tissue late effects that are observed in the lung at low external doses and in the whole body from the internal exposure that occurs as a result of a radiological and/or nuclear dispersion event. An important, but inadequately addressed, aspect of such an event is that radiation exposure can occur internally, and may be either systemic or highly localized depending on the physical and chemical nature of the radioactive material involved. Particles generated in such events will include a significant proportion of ultra-fine or nano-materials, which have different physical and chemical properties from particles of larger diameter and surface area. This phenomenon needs to be considered when calculating dose and potential target organ systems following particle exposure, and this will be addressed in Specific Aim 2 of this project. Our previous work with external beam irradiation of the lung has led to our paradigm of radiation late effects being dependent upon the "conversation" which takes place between a number of injured cells, rather than the classic concept of a single target cell. In the specific aims for this proposal, we will continue our studies of the lung, extending our examination to the lower doses more likely to be seen in the population after the detonation of a radiological device (Specific Aim 1). In the studies in Specific Aim 2, we will determine the effects of inhaled radionuclide nanoparticles and develop a model that compares such exposures to those observed after external lung irradiation alone, as well as whole body exposures. In the studies in Specific Aim 3, we will use information about the cellular and molecular events that occur following radiation exposure, particularly in terms of the alterations in expression of proinflammatory and profibrotic cytokines and growth factors in conjunction with their genetic context, to design and test agents that could be used to ameliorate the toxic effects of radiation in the lung. Finally, in the experiments in Specific Aim 4, we plan to address the question of the potential for altered sensitivity in the developing organism by examining the pulmonary responses following external beam and internal radiation exposures during postnatal growth.